The objectives of this research proposal are to define some of the factors which regulate the synthesis of bile acids in health and disease. The factors to be studied are: 1) the regulation of cholesterol 7Alpha-hydroxylase, the rate-limiting enzyme of bile acid synthesis and 2) defects of bile acid synthesis in both inherited and acquired conditions. We will determine if cholesterol 7Alpha-hydroxylase is regulated by changes in the hepatic concentration of the enzyme or by changes in the activity state of the enzyme. We will also investigate the role of cytochrome P-450 and cytochrome b5 on the activity of 7Alpha-hydroxylase. If it is found that cholesterol 7Alpha-hydroxylase is regulated by the concentration of the enzyme in the liver we will begin a search for nuclear receptors for bile salts and other sterols. Patients with defects inbile acid synthesis will be studied and the specific metabolic blocks will be characterized. Patients to be studied will include children with Reye's syndrome and adults with alcoholic hepatitis. Both of these conditions have abnormal mitochondria and may have defects in the mitochondrial metabolism of bile acids.